Background

Advanced myelodysplastic syndrome (MDS) and juvenile myelomonocytic leukemia (JMML) are rare hematological malignancies in children. A second allograft is recommended if a relapse occurs after hematopoietic stem cell transplantation, but the outcome is poor.

Objective

We conducted a phase I/II multicenter study to evaluate the safety, pharmacokinetics, and activity of azacitidine in children with relapsed MDS/JMML prior to the second hematopoietic stem cell transplantation.

Methods

Patients enrolled from June 2013 to March 2019 received azacitidine intravenously/subcutaneously once daily on days 1–7 of a 28-day cycle. The MDS and JMML cohorts followed a two-stage design separately, with a safety run-in for JMML. Response and safety data were used to evaluate efficacy and establish the recommended dose. Pharmacokinetics was also analyzed. The study closed prematurely because of low recruitment.

Results

Six patients with MDS and four patients with JMML received a median of three and five cycles, respectively. Azacitidine 75 mg/m² was well tolerated and plasma concentration–time profiles were similar to observed in adults. The most prevalent grade 3–4 adverse event was myelotoxicity. No responses were seen in patients with MDS, but 83% achieved stable disease; four patients underwent an allotransplant. Overall response rate in the JMML cohort was 75% (two complete responses; one partial response) and all responders underwent hematopoietic stem cell transplantation. One-year overall survival was 67% (95% confidence interval 38–100) in MDS and 50% (95% confidence interval 19–100) in JMML.

Conclusions

Azacitidine 75 mg/m² prior to a second hematopoietic stem cell transplantation is safe in children with relapsed MDS/JMML. Although the long-term advantage remains to be assessed, this study suggests that azacitidine is an efficacious option for relapsed JMML.

Clinical Trial Registration

EudraCT 2010-022235-10.

中文翻译：

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阿扎胞苷 (Vidaza®) 治疗复发性晚期 MDS 和 JMML 儿科患者：ITCC 联盟和 EWOG-MDS 小组 I/II 期研究结果（研究 ITCC-015）

背景

晚期骨髓增生异常综合征（MDS）和幼年型粒单核细胞白血病（JMML）是儿童罕见的血液恶性肿瘤。如果造血干细胞移植后出现复发，建议进行第二次同种异体移植，但效果不佳。

客观的

我们进行了一项 I/II 期多中心研究，以评估阿扎胞苷在第二次造血干细胞移植前复发性 MDS/JMML 儿童中的安全性、药代动力学和活性。

方法

2013 年 6 月至 2019 年 3 月入组的患者在 28 天周期的第 1-7 天接受阿扎胞苷静脉/皮下注射，每天一次。MDS 和 JMML 队列分别遵循两阶段设计，并为 JMML 进行安全磨合。反应和安全性数据用于评估疗效并确定推荐剂量。还分析了药代动力学。由于招募人数少，该研究提前结束。

结果

6 名 MDS 患者和 4 名 JMML 患者分别接受了中位数 3 个周期和 5 个周期的治疗。阿扎胞苷 75 mg/m ²耐受性良好，血浆浓度-时间曲线与成人中观察到的相似。最常见的 3-4 级不良事件是骨髓毒性。MDS 患者未见缓解，但 83% 的患者病情稳定；四名患者接受了同种异体移植。JMML 队列的总体缓解率为 75%（两名完全缓解；一名部分缓解），所有缓解者均接受了造血干细胞移植。MDS 的一年总生存率为 67%（95% 置信区间 38-100），JMML 的一年总生存率为 50%（95% 置信区间 19-100）。

结论

在患有复发性 MDS/JMML 的儿童中，第二次造血干细胞移植前服用75 mg/m ^{2阿扎胞苷是安全的。}尽管长期优势仍有待评估，但本研究表明阿扎胞苷是治疗复发性 JMML 的有效选择。

临床试验注册

EudraCT 2010-022235-10。